Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env
Young Do Kwon, Marie Pancera, Priyamvada Acharya, Ivelin S Georgiev, Emma T Crooks, Jason Gorman, M Gordon Joyce, Miklos Guttman, Xiaochu Ma, Sandeep Narpala, Cinque Soto, Daniel S Terry, Yongping Yang, Tongqing Zhou, Goran Ahlsen, Robert T Bailer, Michael Chambers, Gwo-Yu Chuang, Nicole A Doria-Rose, Aliaksandr Druz, Mark A Hallen, Adam Harned, Tatsiana Kirys, Mark K Louder, Sijy O'Dell, Gilad Ofek, Keiko Osawa, Madhu Prabhakaran, Mallika Sastry, Guillaume B E Stewart-Jones, Jonathan Stuckey, Paul V Thomas, Tishina Tittley, Constance Williams, Baoshan Zhang, Hong Zhao, Zhou Zhou, Bruce R Donald, Lawrence K Lee, Susan Zolla-Pazner, Ulrich Baxa, Arne Schön, Ernesto Freire, Lawrence Shapiro, Kelly K Lee, James Arthos, James B Munro, Scott C Blanchard, Walther Mothes, James M Binley, Adrian B McDermott, John R Mascola, Peter D Kwong, Young Do Kwon, Marie Pancera, Priyamvada Acharya, Ivelin S Georgiev, Emma T Crooks, Jason Gorman, M Gordon Joyce, Miklos Guttman, Xiaochu Ma, Sandeep Narpala, Cinque Soto, Daniel S Terry, Yongping Yang, Tongqing Zhou, Goran Ahlsen, Robert T Bailer, Michael Chambers, Gwo-Yu Chuang, Nicole A Doria-Rose, Aliaksandr Druz, Mark A Hallen, Adam Harned, Tatsiana Kirys, Mark K Louder, Sijy O'Dell, Gilad Ofek, Keiko Osawa, Madhu Prabhakaran, Mallika Sastry, Guillaume B E Stewart-Jones, Jonathan Stuckey, Paul V Thomas, Tishina Tittley, Constance Williams, Baoshan Zhang, Hong Zhao, Zhou Zhou, Bruce R Donald, Lawrence K Lee, Susan Zolla-Pazner, Ulrich Baxa, Arne Schön, Ernesto Freire, Lawrence Shapiro, Kelly K Lee, James Arthos, James B Munro, Scott C Blanchard, Walther Mothes, James M Binley, Adrian B McDermott, John R Mascola, Peter D Kwong
Abstract
As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.
Conflict of interest statement
Competing financial interests The authors declare no competing financial interests.
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References
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